Discovering empirically conserved amino acid substitution groups in databases of protein families.
This paper introduces a method for identifying empirically conserved amino acid substitution groups. In contrast with existing approaches that view amino acid substitution as a pairwise phenomenon, the method presented here identifies conserved groups of amino acids using a data structure called a conditional distribution matrix. The conditional distribution matrix extends the concept of a pairwise substitution matrix by changing the context of substitution from a single amino acid to a group of amino acids. The matrix tabulates information from a database of protein families that contains numerous aligned positions. Each row in the matrix contains the distribution of amino acids in those aligned positions that contain a given conditioning group of amino acids. The method converts a database of protein families into a conditional distribution matrix and then examines each possible substitution group for evidence of conservation. The algorithm is applied to the BLOCKS and HSSP databases. Twenty amino acid substitution groups are found to be conserved empirically in both databases. These groups provide insight into biochemical properties that are conserved in protein evolution.


Foraging on individual leaves by an intracellular feeding insect is not associated with leaf biomechanical properties or leaf orientation.
Nearly all herbivorous arthropods make foraging-decisions on individual leaves, yet systematic investigations of the adaptive significance and ecological factors structuring these decisions are rare with most attention given to chewing herbivores. This study investigated why an intracellular feeding herbivore, Western flower thrips (WFT) Frankliniella occidentalis Pergande, generally avoids feeding on the adaxial leaf surface of cotton cotyledons. WFT showed a significant aversion to adaxial-feeding even when excised-cotyledons were turned up-side (abaxial-side 'up'), suggesting that negative-phototaxis was not a primary cause of thrips foraging patterns. No-choice bioassays in which individual WFT females were confined to either the abaxial or adaxial leaf surface showed that 35% fewer offspring were produced when only adaxial feeding was allowed, which coincided with 32% less plant feeding on that surface. To test the hypothesis that leaf biomechanical properties inhibited thrips feeding on the adaxial surface, we used a penetrometer to measure two variables related to the 'toughness' of each leaf surface. Neither variable negatively co-varied with feeding. Thus, while avoiding the upper leaf surface was an adaptive foraging strategy, the proximate cause remains to be elucidated, but is likely due, in part, to certain leaf properties that inhibit feeding.


Ultrasound-assisted extraction of phenolic antioxidants from Acacia confusa flowers and buds.
Acacia confusa Merr. (Leguminosae), a species native to Taiwan, is widely distributed on the hills and lowlands of Taiwan, and has been used in traditional medicines. In this study, the application of ultrasound-assisted extraction was used to extract the phenolic compounds from A. confusa flowers and buds for the first time. Among the extraction methods, it can significantly enhance the contents of phenolic compounds and antioxidant activities in A. confusa flower and bud extracts using ultrasound-assisted extraction (10 min×12 times). Considering both the solvent consumption and the time needed for extraction, ultrasound-assisted extraction was found to be the most practical approach for the rapid and efficient extraction of bioactive phenolic constituents. In addition, gallic acid, myricitrin-3-rhamnoside, quercitrin-3-rhamnoside, europetin-3-rhamnoside, kaempferol-3-rhamnoside, rhamnetin-3-glucoside, and rhamnetin-3-rhamnoside were also quantified in different extracts by RP-HPLC. It is clear that ultrasound-assisted extraction is an efficient method for extracting phenolic compounds from A. confusa flowers and buds.


Synthesis of Lactic Acid-Based Thermosetting Resins and Their Ageing and Biodegradability.
The present work is focused on the synthesis of bio-based thermoset polymers and their thermo-oxidative ageing and biodegradability. Toward this aim, bio-based thermoset resins with different chemical architectures were synthesized from lactic acid by direct condensation with ethylene glycol, glycerol and pentaerythritol. The resulting branched molecules with chain lengths (n) of three were then end-functionalized with methacrylic anhydride. The chemical structures of the synthesized lactic acid derivatives were confirmed by proton nuclear magnetic resonance spectroscopy (1H-NMR) and Fourier transform infrared spectroscopy (FT-IR) before curing. To evaluate the effects of structure on their properties, the samples were investigated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and the tensile testing. The samples went through thermo-oxidative ageing and biodegradation; and their effects were investigated. FT-IR and 1H-NMR results showed that three different bio-based resins were synthesized using polycondensation and end-functionalization. Lactic acid derivatives showed great potential to be used as matrixes in polymer composites. The glass transition temperature of the cured resins ranged between 44 and 52 °C. Pentaerythritol/lactic acid cured resin had the highest tensile modulus and it was the most thermally stable among all three resins. Degradative processes during ageing of the samples lead to the changes in chemical structures and the variations in Young's modulus. Microscopic images showed the macro-scale surface degradation on a soil burial test.


Plastidial Expression of 3β-Hydroxysteroid Dehydrogenase and Progesterone 5β-Reductase Genes Confer Enhanced Salt Tolerance in Tobacco.
The short-chain dehydrogenase/reductase (SDR) gene family is widely distributed in all kingdoms of life. The SDR genes, 3β-hydroxysteroid dehydrogenase (3β-HSD) and progesterone 5-β-reductases (P5βR1, P5βR2) play a crucial role in cardenolide biosynthesis pathway in the Digitalis species. However, their role in plant stress, especially in salinity stress management, remains unexplored. In the present study, transplastomic tobacco plants were developed by inserting the 3β-HSD, P5βR1 and P5βR2 genes. The integration of transgenes in plastomes, copy number and transgene expression at transcript and protein level in transplastomic plants were confirmed by PCR, end-to-end PCR, qRT-PCR and Western blot analysis, respectively. Subcellular localization analysis showed that 3β-HSD and P5βR1 are cytoplasmic, and P5βR2 is tonoplast-localized. Transplastomic lines showed enhanced growth in terms of biomass and chlorophyll content compared to wild type (WT) under 300 mM salt stress. Under salt stress, transplastomic lines remained greener without negative impact on shoot or root growth compared to the WT. The salt-tolerant transplastomic lines exhibited enhanced levels of a series of metabolites (sucrose, glutamate, glutamine and proline) under control and NaCl stress. Furthermore, a lower Na+/K+ ratio in transplastomic lines was also observed. The salt tolerance, mediated by plastidial expression of the 3β-HSD, P5βR1 and P5βR2 genes, could be due to the involvement in the upregulation of nitrogen assimilation, osmolytes as well as lower Na+/K+ ratio. Taken together, the plastid-based expression of the SDR genes leading to enhanced salt tolerance, which opens a window for developing saline-tolerant plants via plastid genetic engineering.


Comparison of dentists' treatment and management of normal and handicapped patients.
Forty-eight of 120 dentists (40%) responded to a survey using a two-questionnaire time-series design. Responding dentists with a median age of 36 years and 9.5 years in practice had received education in care of the handicapped mainly in dental school (42%) and continuing education (40%). They were asked to make the same treatment and practice management decisions for both normal and handicapped patients. No significant differences were found between normal and handicapped patients in the amount of time dentists spend on diagnosis, treatment, planning, or recall (p less than 0.05). For both normal and handicapped patients, the dentists as a group always chose the same option as treatment of choice for both normal and handicapped patients most frequently from a list of treatment or management options. Individual dentist consistency between normal and handicapped patients in treatment and management was good, with four out of five dentists choosing the same first treatment of choice for both normal and handicapped patients for similar circumstances. Only about one out of six dentists maintained a consistent priority sequence for both normal and handicapped patients when asked to rank a list of four or five possible treatment or management choices.


Screening and Identification of Potential Hub Genes in Myocardial Infarction Through Bioinformatics Analysis.
Myocardial infarction (MI) is a common cause of death worldwide. It is characterized by coronary artery occlusion that causes ischemia and hypoxia of myocardial cells, leading to irreversible myocardial damage. To explore potential targets for treatment of MI, we reorganized and analyzed two microarray datasets (GSE4648 and GSE775). The GEO2R tool was used to screen for differentially expressed genes (DEGs) between infarcted and normal myocardium. We used the Database for Annotation, Visualization and Integrated Discovery (DAVID) to perform Gene Ontology functional annotation analysis (GO analysis) and the Kyoto Encyclopedia of Genes and Genomes for pathway enrichment analysis (KEGG analysis). We examined protein-protein interactions to characterize the relationship between differentially expressed genes, and we screened potential hub genes according to the degree of connection. PCR and Western blotting were used to identify the core genes. At different times of infarction, a total of 35 genes showed upregulation at all times; however, none of the genes showed downregulation at all 3 times. Similarly, 10 hub genes with high degrees of connectivity were identified. In vivo and in vitro experiments suggested that expression levels of MMP-9 increased at various times after myocardial infarction and that expression increased in a variety of cells simultaneously. Expression levels of MMP-9 increase throughout the course of acute myocardial infarction, and this expression has both positive and negative sides. Further studies are needed to explore the role of MMP-9 in MI treatment. The potential values of Il6, Spp1, Ptgs2, Serpine1, Plaur, Cxcl5, Lgals3, Serpinb2, and Cd14 are also worth exploring.


Recommendations from the European Bioanalysis Forum on method establishment for tissue homogenates.
Tissue analysis has always been a difficult discipline of bioanalysis. Differences in scientific approaches or level of adherence to regulated guidelines have led to a growing ambiguity on how to perform tissue analysis, an ambiguity that starts with the question of if we analyze tissue or tissue homogenates. The European Bioanalysis Forum (EBF) is proposing a recommendation on how to perform method establishment and analysis of tissue homogenates. The recommendation is based on broad discussions and survey data from the EBF community and, as for many EBF recommendations, focuses on finding the right balance between science, technology and regulations.


The predictive validity of the aptitude test for the performance of students starting a medical curriculum.
Selection of medical students varies between German- and French-speaking Swiss faculties. Geneva introduced an aptitude test in 2010, aimed at helping decision making among students. The test was compulsory: it had to be taken by those who intended to register for medical studies. But it was not selective: there was no performance threshold under which registration would have been denied. We followed 353 students who took the test in 2010, checked whether they confirmed their registration for medical studies and studied their performance during year 1 (selective year). The correlation between the aptitude test result and the academic performance during year 1 was 0.47 (n = 191), and weakened to 0.38 (n = 214) when including repetition of year 1. The failure to pass in year 2 or success were associated with the aptitude test results (p <0.001). Overall, 20% of the students succeeded after one year, 26% after a repeated year 1, and 53% failed and could not follow further medical studies. Though there was a clear association between the aptitude test and academic performance, students did not appear to take into account when making their career decisions the ability of the test (as implemented in Geneva, that is, compulsory but not selective) to predict their future performance in the medical programme. The test was withdrawn after the 2012 session, but a number of issues regarding the medical selection procedure remain to be addressed.


Cultural specificity of socioemotional selectivity: age differences in social network composition among Germans and Hong Kong Chinese.
We examined age differences in social network composition among 330 Germans and 330 Hong Kong Chinese, aged 20 to 91 years. We measured social network composition with the Social Convoy Questionnaire. In both cultures, older age was associated with the same number of close social partners and fewer peripheral social partners than was younger age. However, the patterns of age differences in specific relationships differed across cultures: Age was negatively associated with the proportion of nuclear family members among Germans but the association was positive among Hong Kong Chinese. Age was positively associated with the proportion of acquaintances among Germans but the association was negative among Hong Kong Chinese. We discuss the findings in terms of whether the socioemotional selectivity theory holds in both cultures.


Staplers, two- and one-layer manual suturing in gastrointestinal surgery--a retrospective study of 553 patients.
The case histories of all patients with gastrointestinal suturing in a six-year period were studied retrospectively. Anastomoses of the oesophagus, left colon and rectum were always checked radiologically 7-14 days after operation. Suture-line dehiscence, bleeding and stricture formation were seen in 18 cases (= 8.9%) out of 202 patients with stapled suturing, 15 cases (= 7.8%) out of 192 patients with two-layer manual suturing, and 4 cases (= 2.5%) out of 159 patients with one-layer seromuscular manual suturing. After excluding the patients with a pyloroplasty, the adverse factors were comparable in these groups of patients. The suture-line complication rate after one-layer manual suturing (2.5%) proved to be significantly lower than with stapled suturing (9.6%). Reduction in operating time by using the staplers proved to be minimal. The use of staplers is expensive and is not often indicated.


Optimization of multiplexed RADseq libraries using low-cost adaptors.
Reduced representation genomics approaches, of which RADseq is currently the most popular form, offer the possibility to produce genome wide data from potentially any species, without previous genomic information. The application of RADseq to highly multiplexed libraries (including numerous specimens, and potentially numerous different species) is however limited by technical constraints. First, the cost of synthesis of Illumina adaptors including molecular identifiers (MIDs) becomes excessive when numerous specimens are to be multiplexed. Second, the necessity to empirically adjust the ratio of adaptors to genomic DNA concentration impedes the high throughput application of RADseq to heterogeneous samples, of variable DNA concentration and quality. In an attempt to solve these problems, we propose here some adjustments regarding the adaptor synthesis. First, we show that the common and unique (MID) parts of adaptors can be synthesized separately and subsequently ligated, which drastically reduces the synthesis cost, and thus allows multiplexing hundreds of specimens. Second, we show that self-ligation of adaptors, which makes the adaptor concentration so critical, can be simply prevented by using unphosphorylated adaptors, which significantly improves the ligation and sequencing yield.


A Transcriptome Study of Progeroid Neurocutaneous Syndrome Reveals POSTN As a New Element in Proline Metabolic Disorder.
Aging is a complex biological process. A study of pyrroline-5-carboxylate reductase 1 (PYCR1) deficiency, which causes a progeroid syndrome, may not only shed light on its genetic contribution to autosomal recessive cutis laxa (ARCL) but also help elucidate the functional mechanisms associated with aging. In this study, we used RNA-Seq technology to examine gene expression changes in primary skin fibroblasts from healthy controls and patients with PYCR1 mutations. Approximately 22 and 32 candidate genes were found to be up- and downregulated, respectively, in fibroblasts from patients. Among the downregulated candidates in fibroblasts with PYCR1 mutations, a strong reduction in the expression of 17 genes (53.1%) which protein products are localized in the extracellular space was detected. These proteins included several important ECM components, periostin (POSTN), elastin (ELN), and decorin (DCN); genetic mutations in these proteins are associated with different phenotypes of aging, such as cutis laxa and joint and dermal manifestations. The differential expression of ten selected extracellular space genes was further validated using quantitative RT-PCR. Ingenuity Pathway Analysis revealed that some of the affected genes may be associated with cardiovascular system development and function, dermatological diseases and conditions, and cardiovascular disease. POSTN, one of the most downregulated gene candidates in affected individuals, is a matricellular protein with pivotal functions in heart valvulogenesis, skin wound healing, and brain development. Perturbation of PYCR1 expression revealed that it is positively correlated with the POSTN levels. Taken together, POSTN might be one of the key molecules that deserves further investigation for its role in this progeroid neurocutaneous syndrome.


Relationship between HDL Cholesterol Efflux Capacity, Calcium Coronary Artery Content, and Antibodies against ApolipoproteinA-1 in Obese and Healthy Subjects.
To explore the associations between cholesterol efflux capacity (CEC), coronary artery calcium (CAC) score, Framingham risk score (FRS), and antibodies against apolipoproteinA-1 (anti-apoA-1 IgG) in healthy and obese subjects (OS). ABCA1-, ABCG1-, passive diffusion (PD)-CEC and anti-apoA-1 IgG were measured in sera from 34 controls and 35 OS who underwent CAC score determination by chest computed tomography. Anti-apoA-1 IgG ability to modulate CEC and macrophage cholesterol content (MCC) was tested in vitro. Controls and OS displayed similar ABCG1-, ABCA1-, PD-CEC, CAC and FRS scores. Logistic regression analyses indicated that FRS was the only significant predictor of CAC lesion. Overall, anti-apoA-1 IgG were significantly correlated with ABCA1-CEC (r = 0.48, p < 0.0001), PD-CEC (r = -0.33, p = 0.004), and the CAC score (r = 0.37, p = 0.03). ABCA1-CEC was correlated with CAC score (r = 0.47, p = 0.004) and FRS (r = 0.18, p = 0.29), while PD-CEC was inversely associated with the same parameters (CAC: r = -0.46, p = 0.006; FRS: score r = -0.40, p = 0.01). None of these associations was replicated in healthy controls or after excluding anti-apoA-1 IgG seropositive subjects. In vitro, anti-apoA-1 IgG inhibited PD-CEC (p < 0.0001), increased ABCA1-CEC (p < 0.0001), and increased MCC (p < 0.0001). We report a paradoxical positive association between ABCA1-CEC and the CAC score, with the latter being inversely associated with PD in OS. Corroborating our clinical observations, anti-apoA-1 IgG enhanced ABCA1 while repressing PD-CEC, leading to MCC increase in vitro. These results indicate that anti-apoA-1 IgG have the potential to interfere with CEC and macrophage lipid metabolism, and may underpin paradoxical associations between ABCA1-CEC and cardiovascular risk.


Sonographic measurement of fetal humeral soft tissue thickness in pregnancy complicated by GDM.
Sonographic measurement of fetal humeral soft tissue thickness (STT) was performed in 93 women with gestational diabetes mellitus during the third trimester. STT measurements revealed accelerated growth in large for gestational age infants at 31 wk gestation. This new measurement proved to be the most accurate predictor of excessive fetal size compared with other standard ultrasound parameters (sensitivity 82%, specificity 95%, positive predictive value 90%). Asymmetrical growth was more evident in infants with large STT measurements in utero. Humeral STT measurement may distinguish large fetuses with truncal obesity from those that are symmetrically large, thereby allowing prediction of risk for birth trauma before delivery.


Gene expression in Acetabularia. I. Calibration of wheat germ cell-free translation system proteins as internal references for two-dimensional electrophoresis.
Modification of existing two-dimensional techniques enables isoelectric focusing and sodium dodecyl sulphate polyacrylamide gel electrophoresis of complex mixtures of proteins to be completed within 8 h. The method was optimized to separate the protein components of a wheat germ cell-free translation system, providing a statistically proven resolution better than 0 . 03 of a pH unit for the isoelectric point and 1000 for Mr. Fourteen of the more than 300 proteins separated were characterized with respect to Mr and isoelectric point relative to standard proteins under the same conditions. Stained wheat germ proteins thus serve as internal standards for analysis of in vitro translation products.


The efficacy of an internet-based cognitive-behavioral therapy intervention for child anxiety disorders.
To evaluate the efficacy of an Internet-based cognitive-behavioral therapy (CBT) approach to the treatment of child anxiety disorders. Seventy-three children with anxiety disorders, aged 7-12 years, and their parents were randomly assigned to either an Internet-based CBT (NET) or wait-list (WL) condition. Clinical diagnostic assessment and parent and child questionnaires were completed before and after treatment. The NET condition was reassessed at 6-month follow-up. At posttreatment assessment, children in the NET condition showed small but significantly greater reductions in anxiety symptoms and increases in functioning than WL participants. These improvements were enhanced during the 6-month follow-up period, with 75% of NET children free of their primary diagnosis. Internet delivery of CBT for child anxiety offers promise as a way of increasing access to treatment for this population. Future research is needed to examine ways to increase treatment compliance and further enhance the impact of treatment.


Body size and composition of perimenarchal girls.
A number of measurements are reported on a cross-sectional sample of girls who were studied at times ranging from 54 months prior to menarche to 82 months after menarche. Included are anthropometric measurements, lean weight, body fat, abdomen-hip ratio, skeletal size, bone age, muscle strength, and urinary hydroxyproline excretion. The years preceding menarche are associated with an array of physiological and anatomical changes, making it difficult to assign a causative role to any one of them.


Impact of Safety-Net Burden on In-Hospital Mortality and Hospitalization Costs Among Patients with Alcoholic Hepatitis and Alcoholic Cirrhosis.
Alcoholic hepatitis (AH) and alcoholic cirrhosis disproportionately affect ethnic minority and safety-net populations. We evaluate the impact of a hospital's safety net burden (SNB) on in-hospital mortality and costs among patients with AH and alcoholic cirrhosis. We performed a cross-sectional analysis of 2012-2016 National Inpatient Sample. SNB was calculated as percentage of hospitalizations with Medicaid or uninsured payer status. Associations between hospital SNB and in-hospital mortality and costs were evaluated with adjusted multivariable logistic regression and linear regression models. Among 21,898 AH-related hospitalizations, compared to low SNB hospitals (LBH), patients hospitalized in high SNB hospitals (HBH) were younger (44.4 y vs. 47.4 y, P < 0.001) and more likely to be African American (11.3% vs. 7.7%, P < 0.001) or Hispanic (15.4% vs. 8.4%, P < 0.001). AH-related hospitalizations in HBH had a non-significant trend towards higher odds of mortality (OR 1.27, 95% CI 0.98-1.65, P = 0.07) and higher mean hospitalizations costs. Among 108,669 alcoholic cirrhosis-related hospitalizations, patients in HBH were younger (53.3 y vs. 55.8 y, P < 0.001) and more likely to be African American (8.2% vs. 7.3%, P < 0.001) or Hispanic (24.4% vs. 12.0%, P < 0.001) compared to LBH. Compared to alcoholic cirrhosis-related hospitalizations in LBH, mortality was higher among medium SNB (OR 1.10, 95% CI 1.03-1.17, P = 0.007) and HBH (OR 1.07, 95% CI 1.00-1.15, P = 0.05). Mean hospitalization costs were not different by SNB status. HBH hospitals predominantly serve ethnic minorities and underinsured/uninsured populations. The higher in-hospital mortality associated HBH particularly for alcoholic cirrhosis patients is alarming given its increasing burden in the USA.


Liver transplantation, including the concept of reduced-size liver transplants in children.
Since the establishment of a clinical program in liver transplantation in 1984, 162 liver transplants have been performed in 131 patients (78 adults, 53 children). The patient mortality rate while waiting for a suitable organ has been 8% for adults and only 4% for children (25-46% reported in the literature). The low pediatric mortality is a result of the use of reduced-size liver transplants. A total of 14 procedures have been performed in recipients whose clinical condition was deteriorating and for whom no full-size graft could be located. Of 14 children, 13 were less than 3 years of age. Patient survival is 50%, comparable to survival of high-risk recipients of full-size livers. Using reduced-size liver grafting in a transplant program can lower mortality for children awaiting a transplant by overcoming size disparity. Reduced-size liver grafting will allow more effective use of donor resources and provide a potential avenue of research for organ splitting and living related donation.


Flaxseed: its bioactive components and their cardiovascular benefits.
Cardiovascular disease remains the leading cause of mortality and morbidity worldwide. The inclusion of functional foods and natural health products in the diet are gaining increasing recognition as integral components of lifestyle changes in the fight against cardiovascular disease. Several preclinical and clinical studies have shown the beneficial cardiovascular effects of dietary supplementation with flaxseed. The cardiovascular effects of dietary flaxseed have included an antihypertensive action, antiatherogenic effects, a lowering of cholesterol, an anti-inflammatory action, and an inhibition of arrhythmias. Its enrichment in the ω-3 fatty acid α-linolenic acid and the antioxidant lignan secoisolariciresinol diglucoside as well as its high fiber content have been implicated primarily in these beneficial cardiovascular actions. Although not as well recognized, flaxseed is also composed of other potential bioactive compounds such as proteins, cyclolinopeptides, and cyanogenic glycosides, which may also produce biological actions. These compounds could also be responsible for the cardiovascular effects of flaxseed. This article will not only summarize the cardiovascular effects of dietary supplementation with flaxseed but also review its bioactive compounds in terms of their properties, biological effects, and proposed mechanisms of action. It will also discuss promising research directions for the future to identify additional health-related benefits of dietary flaxseed.


Next-generation DNA sequencing offers diagnostic advantages over traditional culture testing.
While the clinical utility of next-generation DNA sequencing (NGS) as a diagnostic tool for infections in humans and traditional pets has been demonstrated, there is a lack of data regarding its utility for exotic animals. For exotic patients, traditional culturing is especially challenging for anaerobic and fungal pathogens. Therefore, diagnosis often relies on PCR, which provides a high degree of sensitivity and specificity, although it targets only a predetermined, finite pathogen panel. NGS provides the same benefits as PCR, while also offering de novo identification and quantification of all bacteria and fungi present in a clinical sample, including novel pathogen discovery. Clinical samples from 78 exotic animal patients were collected simultaneously for conventional culture testing and NGS analysis. Results provided by each laboratory were compared for the presence and absence of bacterial and fungal pathogens and commensals. Results showed large bacterial and fungal species diversity in the study cohort and a lack of sensitivity of microbial culture testing. Culture failed to grow 15% of putative bacterial and 81% of putative fungal pathogens that were identified by NGS. The probability of a "no growth" diagnosis was 14% higher for bacteria and 49% higher for fungi with culture versus NGS testing if fungal culture was conducted. Culture testing failed to diagnose a substantial number of both bacterial and fungal pathogens, which were detected by NGS. This highlights the limitations of traditional culture-based testing and displays the clinically advanced utility of NGS-based diagnostics in exotic animal medicine.


Clinical trial of naltrexone in premenstrual syndrome.
Twenty women with the diagnosis of premenstrual syndrome (PMS) participated in a double-blind, placebo-controlled, crossover study to evaluate the efficacy of naltrexone, an oral opiate antagonist. This study was designed to test the hypothesis that inhibition of opiate withdrawal would aid in the treatment of PMS. The subjects received either placebo or naltrexone from days 9-18 of the cycle for three consecutive cycles. The mean scores of the three day-25 Menstrual Distress Questionnaires of 16 patients on naltrexone were compared with the mean scores of the same patients on placebo. Scores were at least ten points lower on naltrexone in 11 patients and at least ten points higher on naltrexone in two patients. Score changes of less than ten points were noted in the other three patients. The mean scores dropped 28 points on naltrexone (P = .016). The general acceptability of naltrexone was good, with side effects including nausea, decreased appetite, and dizziness. These results suggest that naltrexone alleviates many PMS symptoms and may be an effective treatment for this syndrome.


Emission behavior of dual-side emissive transparent white organic light-emitting diodes.
White organic light-emitting diodes (WOLEDs) resemble light more naturally, with emission spectrum that is comfortable to the human eye. The transparent WOLEDs can be almost invisible by day and can emit a pleasant diffused light at night, allowing the surface light source to shine in both directions, an exciting new lighting technology that could bring new device concepts. However, undesirable angular-dependent emission in transparent WOLEDs is often observed, due to the microcavity effect. In this work, the emission behavior of dual-side emissive transparent WOLEDs was studied experimentally and theoretically. It is found that avoidance of the overlap between the peak wavelengths of the emitters and the resonant wavelength of the organic microcavity moderates the angular-dependent electroluminescence emission behavior, thereby improving the color stability of the transparent white WOLEDs over a broad range of the viewing angle.


The impact of bariatric surgery on retinopathy in patients with type 2 diabetes: a retrospective cohort study.
The impact of bariatric surgery on diabetic retinopathy (DR) is unclear. DR might improve after surgery because of improvement in DR risk factors, but the rapid improvement in hyperglycemia after surgery could worsen DR. To assess the impact of bariatric surgery on the progression to sight-threatening DR (STDR) in patients with type 2 diabetes mellitus (T2DM) and compare STDR progression in patients with T2DM who underwent bariatric surgery with a group of matched patients receiving routine care between January 2005 and December 2012 at a single center. Single-center university hospital. DR was assessed using 2×45-degree retinal images obtained from the English National Diabetic Eye Screening Programme. Only patients who had retinal images within 1 year before surgery and at least 1 image after surgery were included in the analysis. STDR was defined as the presence of preproliferative/proliferative DR, maculopathy, or laser treatment. The comparator group comprised patients with T2DM who attended the same center for diabetes care and who had not undergone bariatric surgery. This analysis comprised 152 patients (mean age, 50.7±8.2 yr; baseline body mass index, 49.0±7.3 kg/m(2)) who were followed-up for 3.0±1.9 years. Of the 141 patients without STDR at baseline, 8 (5.7%) developed STDR by the end of the study. Of 106 patients with no DR at baseline, 2 (1.9%) developed preproliferative DR. Of 41 patients with background DR at baseline, 5 (12.2%) developed preproliferative DR. Of the 143 patients with no maculopathy at baseline, 8 (5.6%) developed maculopathy. Compared with a matched group for age, glycated hemoglobin, and follow-up duration, the progression to STDR and maculopathy was less in patients who underwent surgery versus those who received routine care (STDR: 5.7% [8/141] versus 12.1% [12/99], P = .075; maculopathy: 5.6% [8/143] versus 15.4% [16/104], P = .01, respectively). After bariatric surgery, patients with T2DM remain at risk for developing STDR, even those who did not have evidence of DR before surgery. However, surgery was associated with a lower progression to STDR or maculopathy compared with routine care. Randomized clinical trials are needed to ascertain the impact of bariatric surgery on DR.


TIPICO IX: report of the 9th interactive infectious disease workshop on infectious diseases and vaccines.
The Ninth Interactive Infectious Disease workshop TIPICO was held on November 22-23, 2018, in Santiago de Compostela, Spain. This 2-day academic experience addressed current and topical issues in the field of infectious diseases and vaccination. Summary findings of the meeting include: cervical cancer elimination will be possible in the future, thanks to the implementation of global vaccination action plans in combination with appropriate screening interventions. The introduction of appropriate immunization programs is key to maintain the success of current effective vaccines such as those against meningococcal disease or rotavirus infection. Additionally, reduced dose schedules might improve the efficiency of some vaccines (i.e., PCV13). New vaccines to improve current preventive alternatives are under development (e.g., against tuberculosis or influenza virus), while others to protect against infectious diseases with no current available vaccines (e.g., enterovirus, parechovirus and flaviviruses) need to be developed. Vaccinomics will be fundamental in this process, while infectomics will allow the application of precision medicine. Further research is also required to understand the impact of heterologous vaccine effects. Finally, vaccination requires education at all levels (individuals, community, healthcare professionals) to ensure its success by helping to overcome major barriers such as vaccine hesitancy and false contraindications.


Self-prioritization is supported by interactions between large-scale brain networks.
Resting-state functional magnetic resonance imaging (fMRI) has provided solid evidence that the default mode network (DMN) is implicated in self-referential processing. The functional connectivity of the DMN has also been observed in tasks where self-referential processing leads to self-prioritization (SPE) in perception and decision-making. However, we are less certain about whether (i) SPE solely depends on the interplay within parts of the DMN or is driven by multiple brain networks and (ii) whether SPE is associated with a unique component of interconnected networks or can be explained by related effects such as emotion prioritization. We addressed these questions by identifying and comparing topological clusters of networks involved in self-and emotion prioritization effects generated in an associative-matching task. Using network-based statistics, we found that SPE controlled by emotion is supported by a unique component of interacting networks, including the medial prefrontal part of the DMN (MPFC), frontoparietal network (FPN) and insular salience network (SN). This component emerged as a result of a focal effect confined to few connections, indicating that interaction between DMN, FPC and SN is critical to cognitive operations for the SPE. This result was validated on a separate data set. In contrast, prioritization of happy emotion was associated with a component formed by interactions between the rostral prefrontal part of SN, posterior parietal part of FPN and the MPFC, whereas sad emotion reveals a cluster of the DMN, dorsal attention network (DAN) and visual medial network (VMN). We discussed theoretical and methodological aspects of these findings within the more general domain of social cognition.


Stability and digestibility of encapsulated lycopene in different emulsion systems stabilized by acid-modified soybean lipophilic protein.
Owing to the harsh acidic environment of the stomach, acid-resistant emulsion products have wide-ranging applications in the food industry. Herein, natural soybean lipophilic protein (LP) was used to establish coarse emulsions, nanoemulsions, emulsion gels, and high internal phase Pickering emulsions (HIPPE) under acidic conditions. Furthermore, the carrying characteristics of the acid-resistant emulsion system with lycopene were explored. Comparisons of particle sizes, potentials, microstructures, and rheology of the four carrier systems revealed that HIPPE has a single particle-size distribution, the largest zeta potential, and an elastic gel-like network structure. Comparison of encapsulation rates indicated that HIPPE had the best effect on encapsulating lycopene, reaching approximately 90%. The pH stability, storage stability, and simulated in vitro digestion experiments showed that the four emulsions that were stable under acidic conditions had good acid resistance. Among them, the acid-induced LP-stabilized HIPPE had the best storage stability and superior compatibility with the harsh acidic environment of the stomach, which not only achieved the purpose of delaying the release of lipids but also conferred better protection to lycopene in the gastric tract; moreover, it achieved the best bioavailability. LP-stabilized HIPPE has the best stability and can yield better absorption and utilization of lycopene by the body. The results of this study are helpful for the development of acid-resistant functional emulsion foods that are conducive to the absorption of lycopene. © 2022 Society of Chemical Industry.


Isolation of primary mouse retinal ganglion cells using immunopanning-magnetic separation.
To establish an effective system for isolating primary retinal ganglion cells (RGCs) from newborn mice. The retinas were separated from enucleated eyeballs of Crl:CD-1 mice on postnatal day 1 to 4. RGCs were purified using three different methods, including two-step immunopanning (TSI), direct magnetic separation (DMS), and immunopanning-magnetic separation (IMS). Harvested cells were maintained for 24 h in a defined medium and then examined with immunocytochemistry, western immunoblotting, and real-time reverse transcription polymerase chain reaction (RT-PCR) for glial cell-specific glial fibrillary acidic protein (GFAP) and amacrine cell-specific syntaxin 1. As determined with immunofluorescence staining, RGCs purified by TSI were sparsely mixed with GFAP-positive astrocytes, and RGCs isolated by DMS were frequently mixed with syntaxin 1-positive amacrine cells. However, RGCs collected by IMS were seldom contaminated by GFAP-positive or syntaxin 1-positive cells. On western immunoblots, TSI cells showed significant GFAP expression, and DMS cells showed apparent syntaxin 1 expression, but IMS cells did not. Results of the real-time RT-PCR showed a similar tendency to those of the immunocytochemistry and western immunoblots. Primary mouse RGCs were highly purified by the IMS method, combining the benefits of the TSI and DMS methods. This isolation method may provide a good experimental system for studying glaucoma in vitro.


Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis.
Inflammation may play an important role in cancer progression, and a high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a poor prognostic indicator in several malignancies. Here we quantify the prognostic impact of this biomarker and assess its consistency in solid tumors. A systematic review of electronic databases was conducted to identify publications exploring the association of blood NLR and clinical outcome in solid tumors. Overall survival (OS) was the primary outcome, and cancer-specific survival (CSS), progression-free survival (PFS), and disease-free survival (DFS) were secondary outcomes. Data from studies reporting a hazard ratio and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled hazard ratios were computed and weighted using generic inverse-variance and random-effect modeling. All statistical tests were two-sided. One hundred studies comprising 40559 patients were included in the analysis, 57 of them published in 2012 or later. Median cutoff for NLR was 4. Overall, NLR greater than the cutoff was associated with a hazard ratio for OS of 1.81 (95% CI = 1.67 to 1.97; P < .001), an effect observed in all disease subgroups, sites, and stages. Hazard ratios for NLR greater than the cutoff for CSS, PFS, and DFS were 1.61, 1.63, and 2.27, respectively (all P < .001). A high NLR is associated with an adverse OS in many solid tumors. The NLR is a readily available and inexpensive biomarker, and its addition to established prognostic scores for clinical decision making warrants further investigation.


Whether to push or pull? Nicotine reduction and non-combusted alternatives - Two strategies for reducing smoking and improving public health.
Combustible cigarettes remain the most harmful and addictive tobacco product, and reducing the prevalence of smoking continues to be a critical public health goal. While nicotine is the constituent primarily responsible for addiction to cigarettes, most of the harm associated with smoking comes from byproducts of tobacco combustion. Recently, two different approaches for reducing the harms of smoking have emerged, both of which focus on breaking the link between the addiction to nicotine and the harms caused by smoking. First, the addictive potential of cigarettes could be minimized by requiring a large reduction in the nicotine content of cigarettes. Evidence for a nicotine reduction policy thus far shows that the use of very low nicotine content cigarettes results in a reduction in the number of cigarettes people smoke per day and a reduction in cigarette dependence. Second, emerging alternative nicotine delivery systems (ANDS) like electronic cigarettes may provide sufficient nicotine to act as substitutes for cigarettes while delivering much lower levels of toxicants. Evidence suggests that the emergence of ANDS has increased the percentage of smokers who are able to quit. The present paper will briefly review the evidence for each of these approaches, and consider what contemporary reinforcement and addiction theories can tell us about their likely success. We argue that the most effective endgame approach is one that pursues both nicotine reduction and alternative nicotine delivery systems as complementary.


Indirect computed tomography lymphangiography with aqueous contrast for evaluation of sentinel lymph nodes in dogs with tumors of the head.
Sentinel lymph node evaluation is widely used in human medicine to evaluate the first lymph node(s) to which a tumor drains. Sentinel lymph node biopsy allows avoidance of extensive lymphadenectomies in cases where the sentinel lymph node is negative for metastasis, thereby reducing patient morbidity. It has been shown that regional lymph nodes are not always the sentinel lymph node, thus identification and sampling of sentinel lymph nodes allows for more accurate staging, which is critical for treatment and prognostication in dogs with cancer. The objective of this prospective, pilot study was to determine if indirect computed tomography (CT) lymphangiography with aqueous contrast agent would successfully allow identification of sentinel lymph nodes in dogs with masses on the head. Eighteen dogs underwent CT lymphangiography. The sentinel lymph node was successfully identified within 3 min of contrast injection in 16 dogs (89%). Compression of lymphatic vessels from endotracheal tube ties and/or the patient's own body weight delayed or prevented identification of sentinel lymph nodes in two dogs (11%). Computed tomography lymphangiography with aqueous contrast can be used successfully to rapidly identify sentinel lymph nodes in dogs with masses on the head.


A systematic screen for morphological abnormalities during fission yeast sexual reproduction identifies a mechanism of actin aster formation for cell fusion.
In non-motile fungi, sexual reproduction relies on strong morphogenetic changes in response to pheromone signaling. We report here on a systematic screen for morphological abnormalities of the mating process in fission yeast Schizosaccharomyces pombe. We derived a homothallic (self-fertile) collection of viable deletions, which, upon visual screening, revealed a plethora of phenotypes affecting all stages of the mating process, including cell polarization, cell fusion and sporulation. Cell fusion relies on the formation of the fusion focus, an aster-like F-actin structure that is marked by strong local accumulation of the myosin V Myo52, which concentrates secretion at the fusion site. A secondary screen for fusion-defective mutants identified the myosin V Myo51-associated coiled-coil proteins Rng8 and Rng9 as critical for the coalescence of the fusion focus. Indeed, rng8Δ and rng9Δ mutant cells exhibit multiple stable dots at the cell-cell contact site, instead of the single focus observed in wildtype. Rng8 and Rng9 accumulate on the fusion focus, dependent on Myo51 and tropomyosin Cdc8. A tropomyosin mutant allele, which compromises Rng8/9 localization but not actin binding, similarly leads to multiple stable dots instead of a single focus. By contrast, myo51 deletion does not strongly affect fusion focus coalescence. We propose that focusing of the actin filaments in the fusion aster primarily relies on Rng8/9-dependent cross-linking of tropomyosin-actin filaments.


Differences in mental health problems, coping self-efficacy and social support between adults victimised before and adults victimised after the COVID-19 outbreak: population-based prospective study.
Victims of violence, accidents and threats are at risk for mental health problems. Lower coping self-efficacy and social support levels increase this risk. Although highly relevant, it is unknown if the coronavirus disease 2019 (COVID-19) pandemic amplifies these risks. To examine if the prevalence, incidence and/or mean scores for post-traumatic stress disorder (PTSD), anxiety and depression symptoms, general mental health problems, coping self-efficacy, lack of emotional support and social acknowledgement are higher among adults victimised in the year after the COVID-19 outbreak compared with adults victimised in a similar period before the outbreak. Also, to compare symptoms, problems and support within non-victims during the same period. Data was extracted from four surveys of the VICTIMS study (March 2018, 2019, 2020, 2021), based on a random sample of the Dutch population. Multivariate logistic regression analyses and mixed-effects models were used to examine differences between the two victim groups (2019: n = 421, 2021: n = 319) and non-victims (n = 3245). Adults victimised after the outbreak more often had PTSD, anxiety and depression symptoms, general mental health problems and lower coping self-efficacy than those victimised before. They did not differ in lack of support and acknowledgement. Both victim groups differed from non-victims, where mental health problems and lack of support levels were much lower and almost stable. The COVID-19 pandemic had a negative impact on the mental health and coping self-efficacy levels of victims, whereas mental health problems among non-victims remained virtually stable. Mental healthcare workers, general practitioners and victim services should take this impact into account.


Cucurbit[8]uril-based supramolecular nanocapsules with a multienzyme-cascade antioxidative effect.
A supramolecular nanocapsule was constructed by the ternary host-guest complexation of azobenzene (Azo) and methylviologen (MV) to cucurbit[8]uril (CB[8]) and the subsequent self-assembly. The supramolecular nanocapsule with both glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities can mimic the intracellular enzymatic reactive oxygen species (ROS) defense system.


Integrated backscatter as a fibrosis marker in the metabolic syndrome: association with biochemical evidence of fibrosis and left ventricular dysfunction.
Myocardial fibrosis is an important contributor to heterogeneity of left ventricular (LV) dysfunction in the metabolic syndrome (MS). Comparison of strain with calibrated integrated backscatter (cIB) and serological fibrosis markers could provide a means to understand the association of cardiac function with markers of fibrosis. We studied 172 patients with MS (age 50 ± 13 years) and 61 healthy controls in a prospective, cross-sectional study. Echocardiographic evaluation included myocardial velocities and deformation, and calibrated cIB. Procollagen type III amino-terminal propeptide (PIIINP) and procollagen type I carboxy-terminal propeptide (PICP) were measured from serum. MS patients demonstrated LV systolic and diastolic function, and myocardial echodensity disturbances, as well as elevated serum PIIINP and PICP levels. For most functional variables, calibrated cIB in the basal septum was the strongest determinant of impaired LV performance, independent of higher procollagen levels, LV mass index, age, body mass index, creatinine level, and C-reactive protein. Patients with increased abdominal fat deposit (assessed by the waist-to-hip ratio) presented higher levels of procollagen peptides and septal calibrated cIB, and with more profound LV dysfunction as indicated by lower myocardial deformation and early diastolic velocity, and higher E/e'. Myocardial echodensity is a stronger correlate of LV systolic and diastolic dysfunction in MS, than circulating procollagen peptides. Both fibrosis and LV function abnormalities are increased at a higher waist-to-hip ratio, which might provide a rationale for the implementation of intensified therapy in this subset of patients.


Factors correlating to enhanced surface diffusion in metallic glasses.
The enhancement of surface diffusion (DS) over the bulk (DV) in metallic glasses (MGs) is well documented and likely to strongly influence the properties of glasses grown by vapor deposition. Here, we use classical molecular dynamics (MD) simulations to identify different factors influencing the enhancement of surface diffusion in MGs. MGs have a simple atomic structure and belong to the category of moderately fragile glasses that undergo pronounced slowdown of bulk dynamics with cooling close to the glass transition temperature (Tg). We observe that DS exhibits a much more moderate slowdown compared to DV when approaching Tg, and DS/DV at Tg varies by two orders of magnitude among the MGs investigated. We demonstrate that both the surface energy and the fraction of missing bonds for surface atoms show good correlation to DS/DV, implying that the loss of nearest neighbors at the surface directly translates into higher mobility, unlike the behavior of network-bonded and hydrogen-bonded organic glasses. Fragility, a measure of the slowdown of bulk dynamics close to Tg, also correlates to DS/DV, with more fragile systems having larger surface enhancement of mobility. The deviations observed in the fragility-DS/DV relationship are shown to be correlated to the extent of segregation or depletion of the mobile element at the surface. Finally, we explore the relationship between the diffusion pre-exponential factor (D0) and the activation energy (Q) and compare it to a ln(D0)-Q correlation previously established for bulk glasses, demonstrating similar correlations from MD as in the experiments and that the surface and bulk have very similar ln(D0)-Q correlations.


Improved decision-making and psychophysiological responses in mesial temporal lobe epilepsy after anterior temporal lobectomy.
The somatic marker hypothesis is an influential model of human decision-making postulating that somatic feedback to the brain enhances decision-making in ambiguous circumstances, i.e. when the probabilities of various outcomes are unknown. The somatic feedback can be measured as autonomic responses, which are regulated by the amygdala. The failure to evoke this somatic feedback, which occurs in patients with amygdala lesions, impairs decision-making. The purpose of this study was to investigate the decision-making behaviour of mesial temporal lobe epilepsy patients with pre- and post-epilepsy surgery to ascertain whether the decision-making abilities of groups can be explained by means of the generation of somatic feedback responses. The preoperative group comprised 32 patients with mesial temporal lobe epilepsy due to hippocampal sclerosis, while the postoperative group comprised 23 patients who had undergone anterior temporal lobectomy. The age and gender-matched control group consisted of 30 healthy participants. Decision-making performances were assessed and skin resistance responses were measured simultaneously. The findings of this study reveal that the decision-making performance of preoperative patients with unilateral mesial temporal lobe epilepsy was impaired under conditions of ambiguity, i.e. they did not generate somatic feedback responses before making decisions around ambiguous outcomes, and produced significantly poor scores overall based on a decision-making task. In addition, the resection of epileptogenic limbic structures positively affected the generation of somatic feedback responses, as demonstrated by the significant difference between the magnitudes of autonomic responses of the pre- and post-operative groups. The findings of the study validate the contribution of mesial temporal lobe structures to decision-making behaviour, and also point to the importance of examining the connectivity patterns between the neural structures involved in the decision-making network.


[Mechanism of the anti-alcohol action of fenazepam].
Experiments were performed on 64 albino male rats selected according to their ethanol preference. A long-term administration of ethanol produced a number of specific changes in the activity of the enzymes involved in metabolism of ethanol, lipid peroxidation, enzymes of metabolism of xenobiotics. At the continuous ethanol administration, phenazepam was found to normalize the activity of ethanol-metabolizing enzymes, both in vivo and in vitro. Phenazepam also normalized reaction of lipid peroxidation both in vivo and in vitro. The drug was shown to be an inductor with respect to enzymes of xenobiotic metabolism.


Do pre-burn center management algorithms work? Evaluation of pre-admission diagnosis and treatment adequacy of burn patients referred to a burn center.
Interventions for burn management until the patient is transferred to a burn center affect mortality and morbidity. Therefore, adherence to the developed algorithms is an important issue. This study aimed to determine deficiencies in different aspects of the implementation of these algorithms during the pre-admission diagnosis and treatment processes of patients referred to our burn center. This study involved a four-year review of patients referred to our burn center. 170 burn cases admitted by referral were enrolled in the study. Adequacy of resuscitation within the first 24 hours, adherence to guidlines, and mortality were investigated. Resuscitation performed within the first 24 hours was found to be inadequate in 88 patients (51.8%). When the burned surface area percentages were evaluated all percentages were calculated higher before arrival. There were 78 major burn cases (45.9%), and the frequency of inhalation burns, intubation requirements and renal failure were more common in this group compared to the minor burn group (p<0.001). The frequency of intubation without accurate indications was found to be 70.58% . Inadequate escharotomy was detected at a rate of 52.9% , and inadequate fasciotomy at a rate of 66.6% . The mortality rate was 22.4% among all patients. Interventions undertaken during the period until the patients' referral to these centers affect mortality and morbidity. In this study, it was found that the pre-hopital applications generated were insufficient, and it was proposed that burn patient care algorithms be developed with in-service training throughout the country.


Study design and hierarchy of evidence for surgical decision making.
This article provides a historical overview of the hierarchy of evidence for surgical decision making and discusses key study designs in the hierarchy of evidence. This encompasses meta-analyses, randomized controlled trials, and observational studies, including cohort and case-controlled studies, case series and case reports, and basic science studies. This article also reviews the principles and importance of evidence-based plastic surgery and describes several systems to rate the strength of the scientific evidence.


Climate change decreases aquatic ecosystem productivity of Lake Tanganyika, Africa.
Although the effects of climate warming on the chemical and physical properties of lakes have been documented, biotic and ecosystem-scale responses to climate change have been only estimated or predicted by manipulations and models. Here we present evidence that climate warming is diminishing productivity in Lake Tanganyika, East Africa. This lake has historically supported a highly productive pelagic fishery that currently provides 25-40% of the animal protein supply for the populations of the surrounding countries. In parallel with regional warming patterns since the beginning of the twentieth century, a rise in surface-water temperature has increased the stability of the water column. A regional decrease in wind velocity has contributed to reduced mixing, decreasing deep-water nutrient upwelling and entrainment into surface waters. Carbon isotope records in sediment cores suggest that primary productivity may have decreased by about 20%, implying a roughly 30% decrease in fish yields. Our study provides evidence that the impact of regional effects of global climate change on aquatic ecosystem functions and services can be larger than that of local anthropogenic activity or overfishing.


Assessment of the clinical usefulness of ultrasound-guided cytological specimens obtained from gastrointestinal lesions in dogs and cats.
Cytological biopsies are an integral additional test to an abdominal ultrasound when a lesion is identified, but there is little published on factors that that may impact achieving a clinically useful sample of gastrointestinal lesions obtained by ultrasound-guided fine-needle cytologic biopsy. This retrospective, descriptive study aimed to assess factors that may influence the clinical usefulness of submitted cytological samples collected from gastrointestinal lesions by ultrasound-guided percutaneous fine-needle cytologic biopsy. Gastrointestinal cytological samples obtained from 25 dogs and 19 cats over 2.5 years were reviewed and determined as clinically useful or clinically useless as per the cytology report. Variables dependent on the ultrasound exam that were used in the analysis included lesion location, lesion thickness, loss of gastrointestinal layering, and the number of slides submitted. Thirty (30/44) of the submitted cytological samples were considered clinically useful. Factors associated with achieving a clinically useful sample in univariable models included the number of slides submitted and the thickness of the lesion. However, these two variables appear inter-related, as a weak correlation existed between them. Where histologic biopsies were obtained, a clinically useful sample had a partial or complete agreement with histology in three of 12 and eight of 12 cases, respectively. Ultrasound-guided fine-needle cytological biopsies of gastrointestinal masses provided a clinically useful sample in two-third of the cases, especially if more slides were provided to the cytologist and thicker lesions were sampled.


Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties.
Exosomes are small secreted vesicles that can transfer their content to recipient cells. In cancer, exosome secretion has been implicated in tumor growth and metastatic spread. In this study, we explored the possibility that exosomal pathways might discard tumor-suppressor miRNA that restricts metastatic progression. Secreted miRNA characterized from isogenic bladder carcinoma cell lines with differing metastatic potential were uncoupled from binding to target transcripts or the AGO2-miRISC complex. In metastatic cells, we observed a relative increase in secretion of miRNA with tumor-suppressor functions, including miR23b, miR224, and miR921. Ectopic expression of miR23b inhibited invasion, anoikis, angiogenesis, and pulmonary metastasis. Silencing of the exocytotic RAB family members RAB27A or RAB27B halted miR23b and miR921 secretion and reduced cellular invasion. Clinically, elevated levels of RAB27B expression were linked to poor prognosis in two independent cohorts of patients with bladder cancer. Moreover, highly exocytosed miRNA from metastatic cells, such as miR23b, were reduced in lymph node metastases compared with patient-matched primary tumors and were correlated with increments in miRNA-targeted RNA. Taken together, our results suggested that exosome-mediated secretion of tumor-suppressor miRNA is selected during tumor progression as a mechanism to coordinate activation of a metastatic cascade.


Glial fibrillary acidic protein synthesized in vitro using messenger RNA from a human glioma cell line.
Messenger RNA (mRNA) extracted from a continuous human glioma cell line grown in culture or as a solid tumor was translated in an mRNA-dependent reticulocyte lysate system. Translation products labeled with [35S]methionine were immunoprecipitated with antiserum specific for glial fibrillary acidic (GFA) protein, separated by one- and two-dimensional polyacrylamide gel electrophoresis and analyzed fluorographically. Immunoprecipitates from both cell culture and tumor mRNA translations had a molecular weight of 49,000 daltons, consistent with GFA protein extracted from human tissue. In two dimensions, the 49,000-dalton band resolved into two to three spots at pH 5.7-5.9, the isoelectric point of GFA protein. Minor lower molecular weight products were detected in fluorographs of heavily overloaded gels or in film exposed for extended periods of time. These data indicate that the GFA protein produced by this glioma cell line is chemically and immunologically similar to normal human GFA protein, which suggests that the primary phenotypic expression of GFA protein in this tumor cell line is not altered by the neoplastic process.


Long-term safety of brodalumab in Japanese patients with plaque psoriasis: An open-label extension study.
Brodalumab, an interleukin-17 receptor A inhibitor, demonstrated rapid and robust efficacy with a favorable safety profile in patients with moderate to severe plaque psoriasis. Here, we present data from a multicenter, open-label extension study in patients with plaque psoriasis with/without psoriatic arthritis who completed 64 weeks of treatment with brodalumab (140 or 210 mg, every 2 weeks [Q2W]). Patients were enrolled to evaluate the long-term safety and efficacy of a modified dose of brodalumab. Eligible patients were switched to a reduced dose of brodalumab (140 mg every 4 weeks on day 1) in the extension study; the dose and dosing interval were modified sequentially at the physician's discretion (minimum 140 mg every 8 weeks and maximum 210 mg Q2W) until drug approval, after which all patients were switched to 210 mg Q2W for postmarketing surveillance. Of the 129 patients enrolled, 107 (82.9%) completed the 108-week or more extension study. All patients had psoriasis that was well controlled with brodalumab treatment on day 1. Improvement in psoriasis-related symptoms, evaluated with the Psoriasis Area and Severity Index, Psoriasis Scalp Severity Index, Dermatology Life Quality Index, Nail Psoriasis Severity Index, and American College of Rheumatology 20, 50 and 70, was maintained during the 108-week extension study. Brodalumab treatment was well tolerated throughout, and no new safety signals were identified. The most commonly reported treatment-related adverse event was nasopharyngitis, followed by influenza and oral candidiasis. No cases of serious candida infection or Crohn's disease were observed in this study. Serious treatment-related adverse events, such as appendicitis, brain abscess, bacterial meningitis, colon cancer, immunoglobulin A nephropathy and tubulointerstitial nephritis, were reported in one patient each. No anti-brodalumab-binding antibodies or brodalumab-neutralizing antibodies were detected in any patient throughout the extension study. Overall, the long-term efficacy and safety of brodalumab were demonstrated over 108 weeks.


Carbon monoxide poisoning mimicking long-QT induced syncope.
Carbon monoxide (CO)poisoning is a rare cause of QT prolongation, and is therefore easily missed. The case of a patient with unexplained syncope and QT prologation on the electrocardiogram that turned out to be related to CO poisoning is reported here. In patients with QT prolongation, uncommon causes also should be looked for.


Spatiotemporal reconstruction of global ocean surface pCO2 based on optimized random forest.
The partial pressure of ocean surface CO2 (pCO2) plays an important role in quantifying the carbon budget and assessing ocean acidification. For such a vast and complex ocean system as the global ocean, most current research practices tend to study the ocean into regions. In order to reveal the overall characteristics of the global ocean and avoid mutual influence between zones, a holistic research method was used to detect the correlation of twelve predictive factors, including chlorophyll concentration (Chlor_a), diffuse attenuation coefficient at 490 nm (Kd_490), density ocean mixed layer thickness (Mlotst), eastward velocity (East), northward velocity (North), salinity (Sal), temperature (Temp), dissolved iron (Fe), dissolved silicate (Si), nitrate (NO3), potential of hydrogen (pH), phosphate (PO4), at the global ocean scale. Based on measured data from the Global Surface pCO2 (LDEO) database, combined with National Aeronautics and Space Administration (NASA) Ocean Color satellite data and Copernicus Ocean reanalysis data, an improved optimized random forest (ORF) method is proposed for the overall reconstruction of global ocean surface pCO2, and compared with various machine learning methods. The results indicate that the ORF method is the most accurate in overall modeling at the global ocean scale (mean absolute error of 6.27μatm, root mean square error of 15.34μatm, R2 of 0.92). Based on independent observations from the LDEO dataset and time series observation stations, the ORF model was further validated, and the global ocean surface pCO2 distribution map of 0.25° × 0.25° for 2010 to 2019 was reconstructed, which is of significance for the global ocean carbon cycle and carbon assessment.


[Investigation of the effect of constructions in hospital environment on the crucial units for immunocompromised patients and the development of opportunistic mold infections].
This study was planned to determine the effect of building constructions in and around our hospital, on the development of opportunistic mold infections in immunocompromised patients hospitalized in bone marrow and kidney transplantation units and haematology and oncology units. Samples were collected from high risk units by an air sampler (Air Ideal) from indoors and outdoors of a total of 43 patient rooms. The most commonly isolated species from indoor air cultures of our hospital were Penicillium spp. (50.6%), Cladosporium spp. (20%), Chrysonilia spp. (11%) and Aspergillus (10.6%) species. When outdoor samples were considered, Penicillium spp. (38.8%) was still in the first line, followed by Cladosporium spp. (24.3%), Paecillomyces spp. (10.7%) and Aspergillus (8.7%) species. There was no statistically significant difference of total colony and spore numbers between the samples obtained from indoor and outdoor air (p > 0.05), indicating the close relation with the construction studies in and around the hospital. Clinical samples including bronchoalveoler lavage (BAL) fluid, sputum, endotracheal aspirate and sinus tissue were collected from the total of 43 patients staying at these air sampled rooms, and eight of them (18.6%) yielded positivity for the growth of molds. Of them four were identified as Penicillium chrysogenum (sputum isolates), two as Aspergillus fumigatus (sputum and BAL isolates), one as Aspergillus flavus (BAL isolate), and one as Valsa sordida (sinus tissue) which is considered as a plant pathogen. A total of 53 sera, BAL, and tissue supernatant samples were screened by ELISA for the presence of galactomannan antigen, and five of the eight patients whose cultures were positive were also found positive for galactomannan antigen. One patient has died due to invasive aspergillosis whose BAL specimen and indoor air sample were positive for A. fumigatus. In evaluation of indoor air samples before and after the change of HEPA filters, statistically significant decrease was detected in total colony and spore numbers between the samples taken before and after the filter changes (p < 0.005). This study has emphasized the importance of examination of mold flora of indoor air and clinical samples of high risk group patients intermittantly, in order to prevent opportunistic mold infections in crucial units especially during hospital constructions.


The phylogenetic position of the Critically Endangered Saint Croix ground lizard Ameiva polops: revisiting molecular systematics of West Indian Ameiva.
The phylogenetic position of the critically endangered Saint Croix ground lizard Ameiva polops is presently unknown and several hypotheses have been proposed. We investigated the phylogenetic position of this species using molecular phylogenetic methods. We obtained sequences of DNA fragments of the mitochondrial ribosomal genes 12S rDNA and 16S rDNA for this species. We aligned these sequences with published sequences of other Ameiva species, which include most of the Ameiva species from the West Indies, three Ameiva species from Central America and South America, and one from the teiid lizard Tupinambis teguixin, which was used as outgroup. We conducted Maximum Likelihood and Bayesian phylogenetic analyses. The phylogenetic reconstructions among the different methods were very similar, supporting the monophyly of West Indian Ameiva and showing within this lineage, a basal polytomy of four clades that are separated geographically. Ameiva polops grouped in a cluster that included the other two Ameiva species found in the Puerto Rican Bank: A. wetmorei and A. exsul. A sister relationship between A. polops and A. wetmorei is suggested by our analyses. We compare our results with a previous study on molecular systematics of West Indian Ameiva.


Association of Childhood Respiratory Status with Adult Occupational Exposures in a Birth Cohort.
Rationale: People with better early-life respiratory health may be more likely to work in occupations with high workplace exposures in adult life compared with people with poor respiratory health. This may manifest as a healthy worker effect bias, potentially confounding the analysis of environmental exposure studies. Objectives: To evaluate associations between lung function in adolescence and occupational exposures at initial adult employment. Methods: The TCRS (Tucson Children's Respiratory Study) is a long-term prospective study of respiratory health beginning at birth. Associations between respiratory function at age 11 years and occupational exposures at first job at age 26 years were evaluated with logistic regression. We calculated percentage predicted values for forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1:FVC ratio, and forced expiratory flow from 25% to 75% of vital capacity at age 11. At the 26-year visit, participants self-reported occupational exposures to dust, smoke, and fumes/gas at first job in a standardized interview. Results: Forced expiratory flow from 25% to 75% of vital capacity and FEV1:FVC ratio at age 11 were positively associated with dust workplace exposures at the first job. Each 10% increase in percentage predicted prebronchodilator FEV1:FVC ratio was associated with 30% higher odds of workplace dust exposure (odds ratio for a 1% increase, 1.03 [95% confidence interval, 1.00-1.06; P = 0.045]). Similar associations were observed for FEV1 and FVC with workplace smoke exposures. We also observed modification by time at job: associations were stronger for those who remained in their jobs longer than 12 months. In addition, those with better function at age 11 were more likely to stay in their jobs longer than 12 months if their first jobs involved exposure to dust. Conclusions: Childhood lung function affects initial career choice. This study supports the premise of the healthy worker effect.


Antigenic analysis of gamonts of Hepatozoon canis purified from leukocytes.
Hepatozoon canis is a tick-borne apicomplexan parasite of dogs that infects neutrophils and parenchymal tissues. To study the antigenic characteristics of this parasite, a technique was devised for the purification of gamonts from peripheral blood neutrophils. White blood cells were separated on Ficoll-Hypaque density gradients and the gamonts were released from the host neutrophils by nitrogen cavitation. The blood used for purification originated from dogs with natural or experimental infections of H. canis with a parasitemia of 1.4-33%. The number of parasites collected ranged from 1.5 X 10(6) to 4.2 X 10(7). Portions of purified gamonts were separated and examined under phase and scanning electron microscopy, and the remaining purified parasites were then used as a source of antigens to characterize the humoral immune response by western blot analysis. Serum antibodies from infected dogs recognized more than 15 gamont antigens, and the antigenic patterns observed with sera from naturally and experimentally infected dogs were nearly similar. Four immunodominant protein bands of relative molecular weights of 107, 88, 63, and 28 kDa were recognized by all of the sera examined. The technique applied here for the isolation of host cell-free gamonts will facilitate studies on antigenic composition and immune responses against H. canis and on antigenic relationships between Hepatozoon from different host species and geographic regions.


Bio-Based Healable 2K PU Textile Coating for Durable Applications.
A biobased healable 2K polyurethane (PU) coating incorporating a Schiff base was synthesized and applied as a thin coating on textiles. The Schiff base, made out of cystine and vanillin, contained reversible imine and disulfide bonds and was used as a chain extender in PU synthesis. The FT-IR analysis indicated the successful incorporation of the Schiff base in the PU backbone. Compared with control PU coatings, the healable bio-based PU coating with the Schiff base showed very good healing properties using heat as external stimuli: a healing recovery of 75% was obtained after applying a 2 N scratch and complete recovery of the resistance to hydrostatic pressure. SEM analysis revealed complete closure of the scratch after healing for 30 min at 90 °C. The healing properties are attributed to the synergy of the dual-dynamic metatheses of the imine and disulfide bonds.


Methods and management of the healthy brain study: a large multisite qualitative research project.
To describe processes used in the Healthy Brain project to manage data collection, coding, and data distribution in a large qualitative project, conducted by researchers at 9 universities in 9 states. Project management protocols included: (a) managing audiotapes and surveys to ensure data confidentiality, data tracking and distribution; (b) managing qualitative data to ensure the accuracy and confidentiality of transcription; (c) training in qualitative methods and use of qualitative software; and (d) managing participant survey data and analysis. The project team coded and managed qualitative and survey data for 69 focus groups with more than 500 participants. Multiple interactive training sessions in qualitative data analysis and use of qualitative software (ATLAS.ti) were conducted. To develop a codebook, 2 teams used an open-coding process to identify codes and develop definitions; 2 team members integrated and conceptually organized these results into an initial codebook. For the audio-recordings from each research site, 2 or 3 team members hand coded 1 transcript and calculated interrater agreement (.80 or higher). Using clear protocols, participatory training sessions, team-based coding, and frequent communication among team members via e-mail and regular in-person meetings promotes effective management of large-scale qualitative research projects.


Enhancement of the Raman scattering signal due to a nanolens effect.
The Raman scattering signal of a substrate is investigated using a polystyrene nanolens of a few hundred nanometers inserted within the light path of a confocal microspectrometer. As observed in solid immersion microscopy, the nanolens is at the origin of the improvement of the spatial resolution. Furthermore, enhancement of the Raman scattering signal of the substrate is observed when measuring through the polystyrene bead. The enhancement factors have been measured for silicon, highly ordered pyrolytic graphite, and gallium arsenide substrates. This setup provides a new way of enhancing the Raman signal by means of a nanolens.


The concept of a sensorimotor cortex: its early history, with especial emphasis on two early experimental contributions by W. Bechterew.
A brief account has been given of the events during the last quarter of the nineteenth century which led to the concept of the sensorimotor cortex. An early review by Frederick Mott has served as a useful guide. Particular attention has been paid to two early startlingly prescient papers by W. Bechterew. Since, however, Bechterew changed his views in subsequent publications, he forfeited a major claim for priority, and his early papers were forgotten.


High-intensity meropenem combinations with polymyxin B: new strategies to overcome carbapenem resistance in Acinetobacter baumannii.
The pharmacodynamics of polymyxin/carbapenem combinations against carbapenem-resistant Acinetobacter baumannii (CRAB) are largely unknown. Our objective was to determine whether intensified meropenem regimens in combination with polymyxin B enhance killing and resistance suppression of CRAB. Time-kill experiments for meropenem and polymyxin B combinations were conducted against three polymyxin B-susceptible (MIC of polymyxin B = 0.5 mg/L) CRAB strains with varying meropenem MICs (ATCC 19606, N16870 and 03-149-1; MIC of meropenem = 4, 16 and 64 mg/L, respectively) at 108 cfu/mL. A hollow-fibre infection model was then used to simulate humanized regimens of polymyxin B and meropenem (2, 4, 6 and 8 g prolonged infusions every 8 h) versus N16870 at 108 cfu/mL over 14 days. New mathematical mechanism-based models were developed using S-ADAPT. Time-kill experiments were well described by the mathematical mechanism-based models, with the presence of polymyxin B drastically decreasing the meropenem concentration needed for half-maximal activity against meropenem-resistant populations from 438 to 82.1 (ATCC 19606), 158 to 93.6 (N16870) and 433 to 76.0 mg/L (03-149-1). The maximum killing effect of combination treatment was similar among all three strains despite divergent meropenem MIC values (Emax = 2.13, 2.08 and 2.15; MIC of meropenem = 4, 16 and 64 mg/L, respectively). Escalating the dose of meropenem in hollow-fibre combination regimens from 2 g every 8 h to 8 g every 8 h resulted in killing that progressed from a >2.5 log10 cfu/mL reduction with regrowth by 72 h (2 g every 8 h) to complete eradication by 336 h (8 g every 8 h). Intensified meropenem dosing in combination with polymyxin B may offer a unique strategy to kill CRAB irrespective of the meropenem MIC.


Early computed tomography or focused assessment with sonography in abdominal trauma: what are the leading opinions?
The initial assessment of severely injured patients in the resuscitation room requires a systematic and quickly performed survey. Whereas the Advanced Trauma Life Support (ATLS®)-based algorithm recommends focused assessment with sonography in trauma (FAST) among others, recent studies report a survival advantage of early whole-body computed tomography (WBCT) in haemodynamically stable as well as unstable patients. This study assessed the opinions of trauma surgeons about the early use of WBCT in severely injured patients with abdominal trauma, and abdominal CT in patients with isolated abdominal trauma, during resuscitation room treatment. An online cross-sectional survey was performed over 8 months. Members of the Swiss Society for Surgery and the Austrian and German associations for trauma surgery were invited to answer nine online questions. Overall, 175 trauma surgeons from 155 departments participated. For haemodynamically stable patients, most considered FAST (77.6%) and early CT (82.3%) to be the ideal diagnostic tools. For haemodynamically unstable patients, 93.4% considered FAST to be mandatory. For CT imaging in unstable patients, 47.5% agreed with the use of CT, whereas 52.5% rated early CT as not essential. For unstable patients with pathological FAST and clinical signs, 86.8% agreed to proceed with immediate laparotomy. Most surgeons rely on early CT for haemodynamically stable patients with abdominal trauma, whereas FAST is performed with similar frequency and is prioritized in unstable patients. It seems that the results of recent studies supporting early WBCT have not yet found broad acceptance in the surgical community.


In vitro antiviral activity of aphidicolin and its derivates. Synergistic effects of aphidicolin with other antiviral drugs.
Twenty derivatives of aphidicolin were tested against HSV (herpes simplex virus), HCMV (human cytomegalovirus) and adenovirus in vitro. In addition, the antiviral activity of aphidicolin (CAS 38966-21-1) in combination with aciclovir (CAS 59277-89-3) or cidofovir (CAS 113852-37-2) against HSV was determined. The antiviral effects were evaluated using plaque reduction assay in Vero cells or human Foreskin Fibroblasts (HFF) for HSV and HCMV, respectively. Combination indexes were calculated using the method of Chou and Talalay. Two derivatives (K14254 and K14266) that are considered to be prodrugs of aphidicolin were shown to inhibit HCMV and HSV replication comparably to aphidicolin. None of the tested substances inhibited adenovirus replication. Aphidicolin acted synergistically with aciclovir in a 1:1 molar ratio and with cidofovir in different ratios. Aphidicolin and its two antiviral active derivatives might represent useful additional tools for antiviral therapy of HSV and HCMV infections, especially in combination with clinically used drugs.


Transcriptional regulation of the human P450 oxidoreductase gene: hormonal regulation and influence of promoter polymorphisms.
P450 oxidoreductase (POR) is the flavoprotein that acts as the obligatory electron donor to all microsomal P450 enzymes, including those involved in hepatic drug metabolism as well as three steroidogenic P450 enzymes. The untranslated first exon of human POR was located recently, permitting analysis of human POR transcription. Expression of deletional mutants containing up to 3193 bp of the human POR promoter in human adrenal NCI-H295A and liver Hep-G2 cells located the proximal promoter at -325/-1 bp from the untranslated exon. Common human POR polymorphisms at -208 and -173 had little influence on transcription, but the polymorphism at -152 reduced transcription significantly in both cell lines. EMSA and supershift assays identified binding of Smad3/Smad4 between -249 and -261 and binding of thyroid hormone receptor-β (TRβ) at -240/-245. Chromatin immunoprecipitation showed that Smad3, Smad4, TRα, TRβ, and estrogen receptor-α were bound between -374 and -149. Cotransfection of vectors for these transcription factors and POR promoter-reporter constructs into both cell types followed by hormonal treatment showed that T(3) exerts major tropic effects via TRβ, with TRα, estrogen receptor-α, Smad3, and Smad4 exerting lesser, modulatory effects. T(3) also increased POR mRNA in both cell lines. Thyroid hormone also is essential for rat liver POR expression but acts via different transcription factor complexes. These are the first data on human POR gene transcription, establishing roles for TRβ and Smad3/4 in its expression and indicating that the common polymorphism at -152 may play a role in genetic variation in steroid biosynthesis and drug metabolism.


Insights into the Structures of Superoxide Reductases from the Symbionts Ignicoccus hospitalis and Nanoarchaeum equitans.
Superoxide reductases (SORs) are enzymes that detoxify the superoxide anion through its reduction to hydrogen peroxide and exist in both prokaryotes and eukaryotes. The substrate is transformed at an iron catalytic center, pentacoordinated in the ferrous state by four histidines and one cysteine. SORs have a highly conserved motif, (E)(K)HxP-, in which the glutamate is associated with a redox-driven structural change, completing the octahedral coordination of the iron in the ferric state, whereas the lysine may be responsible for stabilization and donation of a proton to catalytic intermediates. We aimed to understand at the structural level the role of these two residues, by determining the X-ray structures of the SORs from the hyperthermophilic archaea Ignicoccus hospitalis and Nanoarchaeum equitans that lack the quasi-conserved lysine and glutamate, respectively, but have catalytic rate constants similar to those of the canonical enzymes, as we previously demonstrated. Furthermore, we have determined the crystal structure of the E23A mutant of I. hospitalis SOR, which mimics several enzymes that lack both residues. The structures revealed distinct structural arrangements of the catalytic center that simulate several catalytic cycle intermediates, namely, the reduced and the oxidized forms, and the glutamate-free and deprotonated ferric forms. Moreover, the structure of the I. hospitalis SOR provides evidence for the presence of an alternative lysine close to the iron center in the reduced state that may be a functional substitute for the "canonical" lysine.


Spatially resolved magnetometry using cold atoms in dark optical tweezers.
We use Faraday spectroscopy of atoms confined to crossed hollow beam tweezers to map magnetic fields over 3 millimeters with 200 micron resolution in a single trap loading cycle. The hollow beams are formed using spatial light modulation, and the trap location is scanned using acousto-optic deflectors. We demonstrate the technique by mapping a linear quadrupole magnetic field with 10 nT sensitivity.


Estimating reciprocal partition functions to enable design space sampling.
Reaction rates are a complicated function of molecular interactions, which can be selected from vast chemical design spaces. Seeking the design that optimizes a rate is a particularly challenging problem since the rate calculation for any one design is itself a difficult computation. Toward this end, we demonstrate a strategy based on transition path sampling to generate an ensemble of designs and reactive trajectories with a preference for fast reaction rates. Each step of the Monte Carlo procedure requires a measure of how a design constrains molecular configurations, expressed via the reciprocal of the partition function for the design. Although the reciprocal of the partition function would be prohibitively expensive to compute, we apply Booth's method for generating unbiased estimates of a reciprocal of an integral to sample designs without bias. A generalization with multiple trajectories introduces a stronger preference for fast rates, pushing the sampled designs closer to the optimal design. We illustrate the methodology on two toy models of increasing complexity: escape of a single particle from a Lennard-Jones potential well of tunable depth and escape from a metastable tetrahedral cluster with tunable pair potentials.


Sexually selected traits evolve positive allometry when some matings occur irrespective of the trait.
Positive allometry of secondary sexual traits (whereby larger individuals have disproportionally larger traits than smaller individuals) has been called one of the most pervasive and poorly understood regularities in the study of animal form and function. Its widespread occurrence is in contrast with theoretical predictions that it should evolve only under rather special circumstances. Using a combination of mathematical modeling and simulations, here we show that positive allometry is predicted to evolve under much broader conditions than previously recognized. This result hinges on the assumption that mating success is not necessarily zero for males with the lowest trait values: for example, a male who lacks horns or antlers might still be able to copulate if encountering an unguarded female. We predict the strongest positive allometry when males typically (but not always) compete in large groups, and when trait differences decisively determine the outcome of competitive interactions.


[Growth inhibiting effect of glucocorticoids and progestins on tumor cells in vitro: effect on the rate of phospholipid reversal].
The growth-inhibiting effect of dexamethasone was estimated by the ability of the hormone to inhibit the proliferative activity of in vitro cultured hepatoma 22 cells. The effect of another steroid proliferation inhibitor, progesterone, was studied in primary cell cultures of human uterine carcinoma. The cytostatic effect of dexamethasone was observed only in slowly proliferating cells and was rapidly reversed by stimulation of cell division with fresh sera. Dexamethasone did not induce any conspicuous changes in the rate of 32P incorporation into hepatoma phospholipids. In 9 out of 14 human uterine carcinomas progesterone inhibited, whereas 17 beta-estradiol stimulated the 32P incorporation into phospholipids (phosphatidylinositol and phosphatidylcholine); this effect was manifested already after 15-min incubation of cells with the hormone. The resistance of uterine carcinoma cells to steroids was paralleled, as a rule, with the increase in the basal level of 32P incorporation into the phospholipids typical of actively proliferating cells. It was assumed that the inhibition of phospholipid exchange rate is related to the earliest manifestations of the growth-inhibiting effect of steroid hormones, at least progestins. In its turn, stimulation of the proliferative activity of cells may relieve this effect of steroids, eventually resulting in a temporary decrease of the cell sensitivity to hormones.


Defining the limits of normal conjunctival fornix anatomy in a healthy South Asian population.
Quantifying the extent of conjunctival fibrosis for documentation of progression in conjunctival scarring disease is a clinical challenge. Measurement of forniceal foreshortening facilitates monitoring of these disorders. This study aims (1) to define the limits of the normal human conjunctival fornices and how these alter with age and (2) to provide normative data for upper and lower fornix depths (FDs) and fornix intercanthal distance (FICD) within a healthy South Asian, racially distinct population. Epidemiologic, cross-sectional study. A total of 240 subjects with national origins from South Asia, with no known ocular history and normal adnexal and conjunctival examination, aged 20 to 80 years. An FICD modification of a custom-designed fornix depth measurer (FDM) was validated and used for measurement of both lower and upper FDs together with FICDs in 480 healthy eyes with no ocular comorbidities. Data were analyzed using repeated-measures analysis of variance and presented as means with 95% confidence intervals (CIs). Mean lower and upper FDs and FICD for the entire cohort, stratified according to age decade and sex. For this South Asian population, the overall upper and lower FDs were 15.3 mm (95% CI, 14.9-15.6) and 10.9 mm (95% CI, 10.7-11.1), respectively, with FICD defined as 32.9 mm (95% CI, 32.5-33.4) (upper) and 31.7 mm (95% CI, 31.3-32.1) (lower). With increasing age, a progressive reduction of all measured parameters (P < 0.001) was noted, with female subjects having significantly shallower fornices (upper FD, P < 0.001; lower FD, P < 0.001; upper FICD, P = 0.081; and lower FICD, P = 0.015). This is the first study to define the limits of normal upper FD and FICDs in any population group. Our study demonstrates sex variations and progressive conjunctival shrinkage with age. Although it provides important, objective data for normal forniceal anatomy, further study is recommended in other populations to confirm the generalizability of these data or to enable normal comparative datasets for the assessment of conjunctival scarring disorders among all anthropological groups.


Peripheral laser iridoplasty opens angle in plateau iris by thinning the cross-sectional tissues.
Plateau iris syndrome has been described as persistent angle narrowing or occlusion with intraocular pressure elevation after peripheral iridotomy due to the abnormal plateau iris configuration. Argon laser peripheral iridoplasty (ALPI) is an effective adjunct procedure to treat plateau iris syndrome. Classic theory suggests that the laser causes the contraction of the far peripheral iris stroma, "pulls" the iris away from the angle, and relieves the iris-angle apposition. We report a case of plateau iris syndrome that was successfully treated with ALPI. Spectral domain optical coherence tomography confirmed the angle was open at areas with laser treatment but remained appositionally closed at untreated areas. Further analysis suggested significant cross-sectional thinning of the iris at laser-treated areas in comparison with untreated areas. The findings indicate that APLI opens the angle, not only by contracting the iris stroma, but also by thinning the iris tissue at the crowded angle. This is consistent with the ALPI technique to aim at the iris as far peripheral as possible. This case also suggests that spectral domain optical coherence tomography is a useful adjunct imaging tool to gonioscopy in assessing the angle condition.


Taking KLF9 to "Cort" for crimes against metabolism.
Glucocorticoids (GCs) are essential for proper glycemic control, but in excess, can lead to hyperglycemia and diabetes. In this issue of the JCI, Cui et al. elucidate a mechanism by which GCs regulate gluconeogenesis utilizing the transcription factor Krüppel-like factor 9 (KLF9) in physiology and disease settings. They report that KLF9 is a GC-inducible factor that ultimately increases the transcription of proliferator-activated receptor γ coactivator 1 α (PGC1α), resulting in gluconeogenesis. Given the high incidence of GC-induced diabetes, identification of this signaling axis provides, not only critical scientific insight, but also a foundation for preventative therapies for patients receiving chronic GC treatment.


Inhibitory effect of Lactobacillus reuteri on periodontopathic and cariogenic bacteria.
The interaction between Lactobacillus reuteri, a probiotic bacterium, and oral pathogenic bacteria have not been studied adequately. This study examined the effects of L. reuteri on the proliferation of periodontopathic bacteria including Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Porphyromonas gingivalis, and Tannerella forsythia, and on the formation of Streptococcus mutans biofilms. Human-derived L. reuteri strains (KCTC 3594 and KCTC 3678) and rat-derived L. reuteri KCTC 3679 were used. All strains exhibited significant inhibitory effects on the growth of periodontopathic bacteria and the formation of S. mutans biofilms. These antibacterial activities of L. reuteri were attributed to the production of organic acids, hydrogen peroxide, and a bacteriocin-like compound. Reuterin, an antimicrobial factor, was produced only by L. reuteri KCTC 3594. In addition, L. reuteri inhibited the production of methyl mercaptan by F. nucleatum and P. gingivalis. Overall, these results suggest that L. reuteri may be useful as a probiotic agent for improving oral health.